Abstract People with inflammatory airway disease suffer the signs and symptoms of a dysregulated vagal sensory nervous system. These signs and symptoms include inappropriate reflex bronchospasm and secretion that can severely compromise lung function, subacute, and in some cases chronic, urge to cough, and dyspnea sensations ill-matched to lung function. The vagal sensory nerves that lead to these problems are by in large the sensory nociceptive C-fibers that innervated the airways from the larynx to the alveoli. While it is clear that inflammation leads to activation of vagal C-fibers, our understanding of which inflammatory mediators are the most relevant in leading to this activation is very limited. Our understanding of the ionic mechanisms by which the inflammatory mediators activate the C-fibers is also lacking. We have developed the approach that allows us to quantify the all the genes that are expressed in the two major types of vagal C-fiber neurons that specifically innervate the respiratory tract by using deep RNA sequencing of identified neurons. In AIM 1 we will carry out such analysis and provide for the first time a complete characterization of the expression of receptors for inflammatory mediators (cytokines, chemokine, autacoids, TLRs, etc.) by airway-specific vagal C- fiber neurons. In Aim 2 we will use sate-of- the-art electrophysiological techniques to characterize the ability of activating those receptors that are expressed to evoke action potential discharge or increase the excitability of the C-fibers within the airways. In Aim 3 we will address out hypothesis that signaling evoked by stimulation of various receptors for inflammatory mediators converge on a relatively limited number of signaling molecules and ion channels to evoke activation and/or sensitization. An understanding of the profile of mediator receptors expressed by vagal C-fibers, and some of the unifying mechanisms by which these receptors lead to C-fiber stimulation will provide knowledge that will support novel therapeutic strategies aimed at limiting the suffering of those with inflammatory airways diseases such as asthma, COPD, chronic bronchitis, and pulmonary fibrosis. The new knowledge obtained will also be useful for sensory neurobiologist studying other organ systems where vagal afferent nerves contributes to the visceral pathophysiology (e.g. inflammatory bowl disease, pancreatitis).